Semaphorin 4D (SEMA4D), also known as CD100, is a transmembrane protein that belongs to the semaphorin gene family. SEMA4D is expressed on the cell surface as a homodimer, but upon cell activation SEMA4D can be released from the cell surface via proteolytic cleavage to generate sSEMA4D, a soluble form of the protein, which is also biologically active. See Suzuki et al., Nature Rev. Immunol. 3:159-167 (2003); Kikutani et al., Nature Immunol. 9:17-23 (2008).
SEMA4D is expressed at high levels in lymphoid organs, including the spleen, thymus, and lymph nodes, and in non-lymphoid organs, such as the brain, heart, and kidney. In lymphoid organs, SEMA4D is abundantly expressed on resting T cells but only weakly expressed on resting B cells and antigen-presenting cells (APCs), such as dendritic cells (DCs). Its expression, however, is upregulated in these cells following activation by various stimuli. The release of soluble SEMA4D from immune cells is also increased by cell activation.
SEMA4D has been implicated in the development of autoimmune demyelinating diseases such as multiple sclerosis and certain cancers. The failure of the mammalian nervous system to completely regenerate after injury is a major clinical problem. Neural damage as a result of stroke or trauma to the brain, as well as neurodegenerative diseases such as Alzheimer's disease, are a leading cause of death and disability. While the role of SEMA4D signaling through its receptors, e.g., Plexin-B1, on angiogenesis is well-recognized, the effect of SEMA4D signaling on promoting neurogenesis remains unclear. There remains, therefore, a need to provide a solution to the unmet medical need for therapeutic means of neuroregeneration.